SUMMARY OF WORK Excitation-contraction coupling (ECC) in skeletal muscle is mediated in part by a direct, allosteric interaction between dihydropyridine (DHPR) voltage sensors in the t-tubule membrane and ryanodine receptor (RyR) Ca2+ release channels on the terminal cisternae of the sarcoplasmic reticulum (SR). This interaction cannot account for the kinetics of SR Ca2+ release during voltage clamp depolarizations, which consists of a transient release phase followed by a plateau of sustained release. It has been hypothesized that Ca2+-induced Ca2+ release (CICR) amplifies the voltage-controlled release, giving rise to the transient phase; this would be compatible with the ultrastructural evidence that only 1/2 of the RyR's are directly coupled to DHPR's. CICR is an intrinsically self-reinforcing phenomenon, which is paradoxical since SR Ca2+ release remains under continuous, graded control by t-tubule voltage at all times. Because RyR are grouped in dense linear arrays along the t-tubule, CICR channels can be activated by Ca2+ released from neighboring CICR channels as well as that from voltage-controlled channels. The interaction between the stochastic gating of channels in the array and the local diffusion of Ca2+ must give rise to a complex process whose consequences cannot be appreciated by unaided intuition. To help understand this process, we developed a mathematical technique to simulate numerically the stochastic dynamics of diffusion-coupled arrays of RyR's. The simulation revealed that the stochastic interaction of CICR channels allows CICR to be smoothly graded and temporally regulated by the voltage-dependent release, even though the CICR mediated release may be much larger in magnitude. The model reproduced numerous experimentally observed properties of SR Ca2+ release, including the transient/sustained kinetics, the voltage dependence of the release components, the effects of Ca2+ buffers and, most surprisingly, the paradoxical phenomenon of "quantal release," in which a prior conditioning depolarization can suppress release by a subsequent test pulse of lower voltage, but not one of higher voltage. Examination of the detailed workings of the model show that its success depends on collective interactions of mesoscopic (10-60 channel) arrays of release channels, rather than single-channel properties. These arrays, which we term couplons are the functional units of ECC.